Experimental and numerical study of the mixed lubrication under the action of magnetic ionic liquid additives.

In this paper, the tribological characteristics of an oil-soluble magnetic fluid additive under mixed lubrication are studied by experiments and numerical simulation. [bmim][FeCl4] is dissolved in CF10W-40 lubricating oil as a magnetic liquid additive, and its friction coefficient is tested by a point contact friction tester at different temperatures, rotational speeds and magnetic field intensities. The transition condition of lubrication state is obtained through analyzing the Stribeck curves based on the experiments, and the strength model of boundary film is established accordingly. A mixed lubrication model is established by substituting the boundary film strength model and the surface roughness model into the hydrodynamic lubrication model based on Reynolds equation. The results show that the magnetic solution as an additive can obviously reduce friction and wear, and the effect is more obvious under the condition of magnetic field. The boundary film strength model can accurately reflect the transition characteristics of lubrication state in the presence of boundary film, and the mixed lubrication model based on boundary film strength model can more precisely reflect the tribological characteristics of friction pairs, so this study provides a new theoretical method for the related research on the influence of boundary film on lubrication characteristics.

Temperature-Dependent Electrochemical Performance of Ta-Substituted SrCoO3 Perovskite for Supercapacitors.

Developing new electrode materials with good temperature-dependent electrochemical performance has become a great issue for the deployment of hybrid supercapacitors with wide temperature tolerance. In this work, a series of Ta-substituted SrCo1-x Tax O3-δ (x=0.05, 0.10, 0.15, 0.20) perovskites have been studied as positive electrodes for hybrid supercapacitors in terms of their structures, elemental valence states and electrochemical performances. Incorporating Ta into SrCoO3-δ perovskite not only stabilizes the crystallite structure but also notably improves electrochemical activities. The SrCo0.95 Ta0.05 O3-δ @CC delivers the highest specific capacity (Qsp ) of 227.91 C g-1 at 1 A g-1 , which is attributed to the highest oxygen vacancy content and the fastest oxygen diffusion kinetics. The hybrid supercapacitor SrCo0.95 Ta0.05 O3-δ @CC//AC@CC exhibits a high energy density of 22.82 Wh kg-1 @775.09 W kg-1 and a stable long-term cycle life (5000 cycles) with 90.7 % capacity retention. As temperature increases from 25 to 85 °C, the capacitance properties are improved at elevated temperatures for both electrode and device due to the increased electrolyte conductivity. The outstanding electrochemical results present that SrCo1-x Tax O3-δ perovskite holds good prospects for hybrid supercapacitors with wide temperature tolerance.

Flexible All-Solid-State Asymmetric Supercapacitors Based on PPy-Decorated SrFeO3-δ Perovskites on Carbon Cloth.

The defective structure and high oxygen vacancy concentration of SrFeO3-δ perovskite enable fast ion-electron transport, but its low conductivity still hinders the high electrochemical performance. Herein, to enhance the conductivity of SrFeO3-δ-based electrodes, polypyrrole-modified SrFeO3-δ perovskite on carbon cloth (PPy@SFO@CC) has been successfully fabricated by electrodeposition of polypyrrole (PPy) on the surface of SFO@CC. The optimal PPy700@SFO@CC electrode exhibits a specific capacitance of 421 F g-1 at 1 A g-1. It was found that the outside PPy layer not only accelerates the electron transport and ion diffusion but also creates more oxygen vacancies in SrFeO3-δ, enhancing the charge storage performance significantly. Moreover, the NiCo2O4@CC//PPy700@SFO@CC device maintains a specific capacitance of 63.6% after 3000 cycles, which is ascribed to the weak adhesion forces between the active materials and carbon cloth. Finally, the all-solid-state flexible supercapacitor NiCo2O4@CC//PPy700@SFO@CC is constructed with PVA-KOH as the solid electrolyte, delivering an energy density of 16.9 W h kg-1 at a power density of 984 W kg-1. The flexible supercapacitor retains 69% of its specific capacitance after 1000 bending and folding times, demonstrating a certain degree of foldability. The present study opens new avenues for perovskite oxide-based flexible all-solid-state supercapacitors.

The molecular mechanism of WRINKLED1 transcription factor regulating oil accumulation in developing seeds of castor bean.

The transcription factor WRINKLED1 (WRI1), a member of AP2 gene family that contain typical AP2 domains, has been considered as a master regulator regulating oil biosynthesis in oilseeds. However, the regulatory mechanism of RcWRI1 in regulating oil accumulation during seed development has not been clearly addressed. Castor bean (Ricinus communis) is one of the most important non-edible oil crops and its seed oils are rich in hydroxy fatty acids, widely applied in industry. In this study, based on castor bean reference genome, three RcWRIs genes (RcWRI1, RcWRI2 and RcWRI3) were identified and the expressed association of RcWRI1 with oil accumulation were determined. Heterologous transformation of RcWRI1 significantly increased oil content in tobacco leaf, confirming that RcWRI1 activate lipid biosynthesis pathway. Using DNA Affinity Purification sequencing (DAP-seq) technology, we confirmed RcWRI1 binding with Transcription Start Site of genes and identified 7961 WRI1-binding candidate genes. Functionally, these identified genes were mainly involved in diverse metabolism pathways (including lipid biosynthesis). Three cis-elements AW-box ([CnTnG](n)7[CG]) and AW-boxes like ([GnAnC](n)6[GC]/[GnAnC](n)7[G]) bound with RcWRI1 were identified. Co-expression network analysis of RcWRI1 further found that RcWRI1 might be widely involved in biosynthesis of storage materials during seed development. In particular, yeast one hybrid experiments found that both AP2 domains within RcWRI1 were required in binding targeted genes. These results not only provide new evidence to understand the regulatory mechanism of RcWRI1 in regulation of oil accumulation during castor bean seed development, but also give candidate gene resource for subsequent genetic improvement toward increasing oil content in oilseed crops.

Experimental and Numerical Study of the Mixed Lubrication Considering Boundary Film Strength.

For the influence of boundary film on the lubrication state of sliding friction pairs, a boundary film strength model was proposed that can comprehensively reflect the influences of film thickness, pressure, shear stress and temperature. The model parameters were obtained through fitting the test results. Then, a mixed lubrication model considering boundary film strength was established by coupling the boundary film strength model with the hydrodynamic lubrication model and the asperity contact model. The calculation program was developed using the Fortran language, which can effectively capture the tribological characteristics and action ratios of the fluid, boundary film and dry friction components. Simultaneously, the mixed lubrication model was applied to the journal bearing. A parametric analysis was performed to investigate the influences of different working conditions on lubrication performance. Under current operating conditions, the results show that: when the speed is above 200 r/min or the viscosity is higher than 0.09 Pa·s, the boundary film breakdown rate is almost 0 and the friction coefficient is lower than 0.02; when the roughness is reduced from 1.8 µm to 0.8 µm, the ultimate load of the journal bearing rises from 27 MPa to 36 MPa, an increase of about 33%; when the load exceeds 36 MPa or the temperature is higher than 100 °C, more than 25% of the boundary film breaks and the dry friction component accounts for more than 60% of the total friction, which leads to a sudden increase in the friction coefficient. Hence, the study of mixed lubrication considering boundary film strength provides theoretical guidance for accurately reflecting the actual lubrication state and improving the mechanical energy efficiency of friction pairs.

Cefepime, not Piperacillin/Tazobactam use, for empirical treatment of bloodstream infections caused by Enterobacter spp.: Results from a population pharmacokinetic/pharmacodynamic analysis.

OBJECTIVE: There is a paucity of published data to evaluate the efficacy and safety of imipenem, cefepime and piperacillin/tazobactam dosing regimens against bloodstream infections caused by Klebsiella aerogenes (BSIs-Kae) and Enterobacter cloacae complex (BSIs-Ecc) in patients with various degrees of renal function. METHODS: Pathogens were isolated from China's blood bacterial resistant investigation network. The dosing regimens of imipenem, cefepime and piperacillin were simulated with intermittent infusion and extended infusion. Monte Carlo simulation was performed to calculate the probability of target attainment and a cumulative fraction of response (CFR) against BSIs-Kae/Ecc. RESULTS: In total, 203 BSIs-Kae, and 785 BSIs-Ecc were isolated from the surveillance network. Imipenem showed the highest in vitro activity against BSIs-Kae/Ecc, followed by cefepime (85%) and piperacillin/tazobactam (70-80%). The MIC90 values of imipenem, cefepime and piperacillin/tazobactam aginst BSIs-Kae and BSIs-Ecc were 1/1 mg/L, 16/16 mg/L, and 64/128 mg/L, respectively. The simulation results showed imipenem achieved the highest CFRs in patients with normal or decreased renal function, with values of 91-99%, followed by FEP (88-96%), without risk of excessive dosing. However, the intermittent and extended dosing regimens of piperacillin/tazobactam were unlikely to provide adequate exposure for empirical management of BSIs-Kae/Ecc (CFRs, 50-80%), regardless of renal function. Besides, the traditional intermittent piperacillin/tazobactam dosing regimens were highly likely to contribute to suboptimal therapeutic exposure when MIC was close to clinical breakpoints. CONCLUSIONS: Cefepime, not piperacillin/tazobactam, can be a reasonable carbapenem-sparing option in empirically treating BSIs-Kae/Ecc.

Eukaryotic initiation factor 5A2 mediates hypoxia-induced autophagy and cisplatin resistance.

Hypoxia-induced cisplatin resistance is a major challenge during non-small cell lung cancer (NSCLC) treatment. Based on previous studies, we further explored the effect of eukaryotic initiation factor 5A2 (eIF5A2) in hypoxia-induced cisplatin resistance. In this study, we found that autophagy and cisplatin resistance were increased under hypoxic conditions in three different NSCLC cell lines. Compared with that under normoxic conditions, dramatic upregulation of eIF5A2 and hypoxia inducible factor 1 subunit alpha (HIF-1α) levels were detected under hypoxia exposure. Small interfering RNA silencing of HIF-1α resulted in decreased expression of eIF5A2, indicating that eIF5A2 acts downstream of HIF-1α. In addition, the expression of eIF5A2 was significantly higher in NSCLC tumors compared with that in normal tissues. RNA silencing-mediated downregulation of eIF5A2 decreased hypoxia-induced autophagy, thereby reducing hypoxia-induced cisplatin resistance in NSCLC cells. The roles of eIF5A2 in cisplatin resistance were further validated in vivo. Combined treatment using eIF5A2-targeted downregulation together with cisplatin significantly inhibited tumor growth compared with cisplatin alone in the subcutaneous mouse model. In conclusions, eIF5A2 overexpression is involved in hypoxia-induced autophagy during cisplatin resistance. We suggest that a combination of eIF5A2 targeted therapy and cisplatin chemotherapy is probably an effective strategy to reverse hypoxia-induced cisplatin resistance and inhibit NSCLC development.

Metabolomic and transcriptomic analyses reveal new insights into the role of abscisic acid in modulating mango fruit ripening.

Mango (Mangifera indica L.) is a climacteric tropical fruit consumed around the world. Although ethylene and abscisic acid (ABA) have been considered to be stimulators that trigger mango fruit ripening, their regulation mechanisms in modulating mango fruit ripening remain uncertain. In this study, we performed integrative analyses of metabolome and transcriptome data combined with a series of physiological and experimental analyses in the 'Keitt' mango, and we characterized changes in accumulation of specific metabolites at different stages during fruit development and ripening, which were strongly correlated with transcriptional changes and embodied physiological changes as well as taste formation. Specifically, we found that ABA, rather than ethylene, was highly associated with mango ripening, and exogenous ABA application promoted mango fruit ripening. Transcriptomic analysis identified diverse ripening-related genes involved in sugar and carotenoid biosynthesis and softening-related metabolic processes. Furthermore, networks of ABA- and ripening-related genes (such as MiHY5, MiGBF4, MiABI5, and MibZIP9) were constructed, and the direct regulation by the key ABA-responsive transcription factor MiHY5 of ripening-related genes was experimentally confirmed by a range of evidence. Taken together, our results indicate that ABA plays a key role in directly modulating mango fruit ripening through MiHY5, suggesting the need to reconsider how we understand ABA function in modulating climacteric fruit ripening.

Comparative Transcriptomics Analysis of Roots and Leaves under Cd Stress in Calotropis gigantea L.

Calotropis gigantea is often found in mining areas with heavy metal pollution. However, little is known about the physiological and molecular response mechanism of C. gigantea to Cd stress. In the present study, Cd tolerance characteristic of C. gigantea and the potential mechanisms were explored. Seed germination test results showed that C. gigantea had a certain Cd tolerance capacity. Biochemical and transcriptomic analysis indicated that the roots and leaves of C. gigantea had different responses to early Cd stress. A total of 176 and 1618 DEGs were identified in the roots and leaves of C. gigantea treated with Cd compared to the control samples, respectively. Results indicated that oxidative stress was mainly initiated in the roots of C. gigantea, whereas the leaves activated several Cd detoxification processes to cope with Cd, including the upregulation of genes involved in Cd transport (i.e., absorption, efflux, or compartmentalization), cell wall remodeling, antioxidant system, and chelation. This study provides preliminary information to understand how C. gigantea respond to Cd stress, which is useful for evaluating the potential of C. gigantea in the remediation of Cd-contaminated soils.

Identification of an Autophagy-Related lncRNA Prognostic Signature and Related Tumor Immunity Research in Lung Adenocarcinoma.

Autophagy is closely associated with the tumor immune microenvironment (TIME) and prognosis of patients with lung adenocarcinoma (LUAD). In the present study, we established a signature on the basis of long noncoding RNAs (lncRNAs) related to autophagy (ARlncRNAs) to investigate the TIME and survival of patients with LUAD. We selected ARlncRNAs associated with prognosis to construct a model and divided each sample into different groups on the basis of risk score. The ARlncRNA signature could be recognized as an independent prognostic factor for patients with LUAD, and patients in the low-risk group had a greater survival advantage. Kyoto Encyclopedia of Genes and Genomes and Gene Ontology enrichment analysis suggested that several immune functions and pathways were enriched in different groups. A high-risk score correlated significantly negatively with high abundance of immune cells and stromal cells around the tumor and high tumor mutational burden. Low-risk patients had a higher PD-1, CTLA-4, and HAVCR2 expression and had a better efficacy of immune checkpoint inhibitors, including PD-1/CTLA-4 inhibitor. A reliable signature on the basis of ARlncRNAs was constructed to explore the TIME and prognosis of patients with LUAD, which could provide valuable information for individualized LUAD treatment.

Construction of an immune-related lncRNA signature as a novel prognosis biomarker for LUAD.

The tumor immune microenvironment of lung cancer is associated with prognosis and immunotherapy efficacy. Long noncoding RNAs are identified as prognostic biomarkers associated with immune functions. We constructed a signature comprising differentially expressed immune-related lncRNAs to predict the prognosis of patients with lung adenocarcinoma. We established the immune-related lncRNA signature by pairing immune-related lncRNAs regardless of expression level and lung adenocarcinoma patients were divided into high- and low-risk groups. The prognosis of patients in the two groups was significantly different; The immune-related lncRNA signature could serve as an independent lung adenocarcinoma prognostic indicator. The signature correlated negatively with B cell, CD4+ T cell, M2 macrophage, neutrophil, and monocyte immune infiltration. Patients with low risk scores had a higher abundance of immune cells and stromal cells around the tumor. Gene set enrichment analysis showed that samples from low-risk group were more active in the IgA production in intestinal immune network and the T and B cell receptor signaling pathway. High-risk groups had significant involvement of the cell cycle, DNA replication, adherens junction, actin cytoskeleton regulation, pathways in cancer, and TGF-ß signaling pathways. High risk scores correlated significantly negatively with high CTLA-4 and HAVCR2 expression and higher median inhibitory concentration of common anti-tumor chemotherapeutics (e.g., cisplatin, paclitaxel, gemcitabine) and targeted therapy (e.g., erlotinib and gefitinib). We identified a reliable immune-related lncRNA lung adenocarcinoma prognosis model, and the immune-related lncRNA signature showed promising clinical prediction value.

Genomic insights into the origin, domestication and genetic basis of agronomic traits of castor bean.

BACKGROUND: Castor bean (Ricinus communis L.) is an important oil crop, which belongs to the Euphorbiaceae family. The seed oil of castor bean is currently the only commercial source of ricinoleic acid that can be used for producing about 2000 industrial products. However, it remains largely unknown regarding the origin, domestication, and the genetic basis of key traits of castor bean. RESULTS: Here we perform a de novo chromosome-level genome assembly of the wild progenitor of castor bean. By resequencing and analyzing 505 worldwide accessions, we reveal that the accessions from East Africa are the extant wild progenitors of castor bean, and the domestication occurs ~ 3200 years ago. We demonstrate that significant genetic differentiation between wild populations in Kenya and Ethiopia is associated with past climate fluctuation in the Turkana depression ~ 7000 years ago. This dramatic change in climate may have caused the genetic bottleneck in wild castor bean populations. By a genome-wide association study, combined with quantitative trait locus analysis, we identify important candidate genes associated with plant architecture and seed size. CONCLUSIONS: This study provides novel insights of domestication and genome evolution of castor bean, which facilitates genomics-based breeding of this important oilseed crop and potentially other tree-like crops in future.

Clinical characteristics and gene mutation analysis of clear cell tumor of the lung.

There were rare clinical reports on clear cell tumor of the lung (CCTL). The clinical characteristics and underlying genetic mutation status of CCTL are poorly understood. From 2012 to 2017, patients pathologically diagnosed with CCTL in our hospital were investigated and analyzed based on clinical manifestations, pathological characteristics, prognosis and full gene mutation status through next generation sequencing (NGS) technology. During a 6-year period, four eligible patients were diagnosed with CCTL through surgical resection and were included in this study. All patients showed solitary nodules or lumps located in the left lung. The average maximum diameter of lesions was 2.5 ± 1.1 cm. Computed tomography (CT) imaging characteristics of these nodules/lumps demonstrated the features of benign tumors. The hematoxylin-eosin (HE) morphology and immunohistochemistry were consistent with the histopathological features of benign CCTL. Subsequent NGS analysis showed frame shift mutations of F2421/E2419, K1466E mutation, and p. 1450_1456 deletion mutation in mTOR gene in two of four patient samples and amplifications of MCL1 were observed in three of four samples. CCTL is a rare type of primary pulmonary mesenchymal tumor with good prognosis. Preliminary diagnosis on CT is usually sclerosing pneumocytoma. It is still unclear whether the occurrence and development of the disease are related to specific gene mutation. In this study, the genomic findings of frame shift mutation of mTOR genes and amplification of MCL1 gene in CCTL suggest that these mutations might play a role in proliferation of CCTL.

Tailing effect of PD-1 antibody results in the eradication of unresectable multiple primary lung cancer presenting as ground-glass opacities: a case report.

There is currently no standard treatment for multiple primary lung cancer (MPLC). We report a case of synchronous MPLC presenting as one ground-glass opacity (GGO) with predominant consolidation accompanied by at least parietal pleura involvement, and another with >30 GGOs distributed across bilateral lungs, which was ineligible for complete resection. CT-guided percutaneous biopsy of the nearly pure-solid mass showed invasive lung adenocarcinoma mainly composed of acinar type. Capture-based, ultra-deep targeted sequencing (Burning Rock, Guangzhou, China) was performed on the tumor tissue biopsy. The result revealed no druggable mutations according to the guideline and a high TMB of 34.1 Mb. Immunohistochemical staining (22C3; Dako, Denmark) was positive for PD-L1 expression with a tumor expression level of 30%. Based on the clinical information and patient's decision, he received 3 cycles of pemetrexed plus pembrolizumab and was subsequently forced to withdraw due to acquired immune-related pneumonitis. After discontinuation of corticosteroids, he was subjected to wedge resection for the nearly pure-solid lesion, and then refused further treatment for the other tumors. After a follow-up of 12 months from termination of immunotherapy, almost all GGOs achieved radiographically complete remission, attributed to the tailing effect of the programmed cell death protein 1 (PD-1) antibody of pembrolizumab. Through the case study we found that unresectable synchronous MPLC presenting as GGOs may respond well to immunotherapy.

Saikosaponin D inhibits proliferation and induces apoptosis of non-small cell lung cancer cells by inhibiting the STAT3 pathway.

OBJECTIVE: To study the effects of saikosaponin D (SSD) on proliferation and apoptosis in human non-small cell lung cancer cell lines, and to explore underlying mechanisms. METHODS: Following treatment with saikosaponin D, A549 and H1299 cells were assessed for anti-proliferation effects using cell cycle kit-8 assays, changes in nuclear morphology using 4',6-diamidino-2-phenylindole (DAPI) staining, and cell apoptosis using annexin V/propidium iodide double staining. Proliferation- and apoptosis-related proteins were detected by immunoblotting. RESULTS: Saikosaponin D had dose-dependent inhibitory effects on A549 cells (IC50, 3.57 µM) and H1299 cells (IC50, 8.46 µM). DAPI staining revealed decreased cell numbers, and most H1299 cells became round after treatment with 20 µM saikosaponin D. As saikosaponin D concentration increased, the proportions of cells in G0/G1 phase, and cells undergoing apoptosis, increased. Levels of phosphorylated p44/42 and signal transducer and activator of transcription (STAT)3 were significantly downregulated in both cell lines, while total STAT3 levels were not significantly affected. The cleaved form of caspase 3 was significantly upregulated. CONCLUSIONS: Saikosaponin D inhibits proliferation, inducing cell cycle arrest and apoptosis, in lung cancer cells in a dose-dependent manner, possibly through inhibition of STAT3 phosphorylation and activation of caspase 3.

High-level gain of mesenchymal-epithelial transition factor (MET) copy number using next-generation sequencing as a predictive biomarker for MET inhibitor efficacy.

BACKGROUND: In clinical oncology, targeted next-generation sequencing (NGS) has become an integral part of the routine molecular diagnostics repertoire. However, a consensus is yet to be agreed on the optimal mesenchymal-epithelial transition factor (MET) copy number (CN) cut-off value based on NGS data that could predict the MET-amplified non-small cell lung cancer (NSCLC) patients who could benefit from MET tyrosine kinase inhibitor (TKI) therapy. In this study, we aimed to identify the criteria to define MET amplification derived from NGS data. METHODS: Sequencing data from matched plasma and tissue samples from 40 MET-amplified NSCLC patients were used to derive a normalization method, referred to as adjusted copy number (adCN). Clinical outcomes from an additional 18 MET TKI-treated NSCLC patients with solely MET-amplified cancers were analyzed to validate the adCN cut-offs. RESULTS: AdCN, calculated as the absolute CN generated from NGS relative to the maximum mutant allele fraction (maxMAF) per sample, was demonstrated to have a high correlation with MET CN in tissue and plasma samples (R2=0.73). Using a cut-off value of 5.5 and 13, tertile stratification of adCN was able to distinguish patients with high-level MET amplification. The MET TKI-treated patients with adCN >13, categorized as high-level amplification, had significantly longer progression-free survival (PFS) than those with adCN <13 (P=0.009), suggesting that adCN positively correlated with the response to MET TKI. CONCLUSIONS: We derived a normalization method that could reflect the relative CN and distinguish MET-amplified NSCLC patients with high-level gene amplification who were sensitive to crizotinib, suggesting adCN could potentially serve as a predictive biomarker for MET TKI response.

Isolated sigmoid colon metastasis from lung micropapillary adenocarcinoma: a case report.

Lung cancer is a common malignant neoplasm that is prone to distant metastasis. Gastrointestinal metastasis from lung cancer is rather rare no matter what stage. Herein, we presented a case of pulmonary adenocarcinoma six months after thoracoscopic Lobectomy isolated metastasis to sigmoid colon. Then the patient underwent radical resection of metastatic tumors of sigmoid colon. The pathologic morphology and immunohistochemistry of lung adenocarcinoma is highly consistent with the sigmoid colon tumor and their gene profiles are likely similar expect for an AXIN1 mutation in primary tumor and not in the metastatic lesion.

Crizotinib induces apoptosis of lung cancer cells through JAK-STAT pathway.

Effect of crizotinib on apoptosis of lung cancer cells was investigated. Human non-small cell lung adenocarcinoma H2228 cells were cultured in the presence of 0, 20, 40, 80, 160 and 320 nmol/l of crizotinib for 3 days, respectively. The inhibition rate of cell proliferation was measured by MTT assay, and half maximal inhibitory concentration (IC50) was calculated. Cell apoptosis was detected by flow cytometry. Transwell assay was performed to detect cell migration. Expression of Janus protein tyrosine kinase (JAK) and signal transducer and activator of transcription (STAT) proteins was detected by western blot analysis. Crizotinib significantly inhibited the proliferation of human lung cancer H2228 cells, and the inhibitory effect was enhanced with the increase of the concentration of crizotinib (p<0.01). The IC50 value was 311.26 nnol/l. According to IC50 value, concentration of crizotinib at 300 nmol/l was selected for the study. It was found that crizotinib at 300 nmol/l significantly promoted cell apoptosis (p<0.01) and inhibited cell migration (p<0.01). Compared with pretreatment levels, crizotinib downregulated the expression of JAK and STAT (p<0.01) on the 1st day of treatment, but with the prolongation of time, no further significant difference was observed on the 1st, 2nd or 3rd day in the level of JAK protein (p=0.47); there were no statistically significant differences in the level of STAT protein (p=0.91). Crizotinib can inhibit the migration and promote cell apoptosis of human lung cancer cell line H2228 by regulating the expression of JAK and STAT proteins in JAK-STAT signaling pathway.

Fatal interstitial lung disease associated with Crizotinib pathologically confirmed by percutaneous lung biopsy in a patient with ROS1-rearranged advanced non-small-cell lung cancer: a case report.

BACKGROUND: Crizotinib is a multi-target inhibitor approved for the treatment of advanced non-small-cell lung cancer patients with a ROS1 rearrangement. However, interstitial lung disease is a rare but severe and fatal side effect of crizotinib that should lead to immediate discontinuation of the drug. Unfortunately, the pathophysiology, molecular mechanism and risk factors for crizotinib-induced interstitial lung disease remain poorly understood. CASE PRESENTATION: We first identified and reported interstitial lung disease induced de novo by crizotinib in a 47-year-old female patient who was diagnosed with advanced lung adenocarcinoma with a ROS1 rearrangement in a malignant pleural effusion. Subsequent next-generation sequencing analysis revealed both ROS1 rearrangement and an EGFR exon 19 deletion mutation in lung biopsy specimens, which were histologically confirmed to be interstitial lung disease. Although crizotinib treatment was ceased immediately and a shock treatment with high-dose methylprednisolone as well as other necessary treatment procedures was applied to reverse the interstitial lung disease process, the patient died. CONCLUSIONS: The present case indicates that while treating non-small-cell lung cancer patients with crizotinib, it is important to constantly monitor any newly emerging respiratory symptoms and unexplained imaging changes, which may suggest an adverse effect related to drug-induced interstitial lung disease or even lethality. Histopathology and molecular pathological examination of lung biopsy specimens may help clinicians understand the development mechanism and exclude other causes.

Correction: Local thoracic therapy improve prognosis for stage IV non-small cell lung cancer patients combined with chemotherapy: A Surveillance, Epidemiology, and End Results database analysis.

[This corrects the article DOI: 10.1371/journal.pone.0187350.].